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<p>Uveal melanoma (UM) is an eye cancer that is fatal upon metastasis to the liver. Most treatments trialed in UM fail to provide therapeutic benefit; thus, there is an urgent need for novel treatment strategies. The MAPK and PI3K signaling pathways, key molecular drivers found to be hyper-activated in UM, converge on the MNK1/2-eIF4E and mTORC1/2-4EBP axes. Here, we demonstrate that the pharmacologic inhibition of MNK1/2 in combination with an mTOR inhibitor impairs clonogenic outgrowth and UM cell invasion. Using proteomic analyses, we reveal that combined MNK1/2 and mTOR inhibition disrupts ER-to-Golgi protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. We further uncover that the knockdown of RAB1A blocks liver metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. Finally, we show that RAB1A expression reshapes the surfaceome by increasing the abundance of plasma membrane proteins associated with poor overall survival in UM, highlighting its potential as a biomarker. This study identifies protein vesicle transport as an unrecognized vulnerability in UM and supports a mechanistic rationale for targeting MNK1/2 and mTOR in metastatic UM.</p><p></p>

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RAB1A is a novel vulnerability in uveal melanoma revealed by dual inhibition of MNK1/2 and mTOR

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月18日

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  • Raúl E. Flores-González,
  • Christophe Goncalves,
  • Noah Wirasinghe,
  • Veronique Gaudreault,
  • Jesus M. Noda Ferro,
  • Kelly Coutant,
  • Andrew Mitchell,
  • Theodore Papadopoulos,
  • Yuen Yi Cho,
  • Elizabeth Guettler,
  • Daniel R. González-Moreno,
  • Samuel Preston,
  • Feiyang Cai,
  • Natascha Gagnon,
  • Steve Jean,
  • Solange Landreville,
  • Wilson H. Miller Jr.,
  • Sonia V. del Rincón

摘要

Uveal melanoma (UM) is an eye cancer that is fatal upon metastasis to the liver. Most treatments trialed in UM fail to provide therapeutic benefit; thus, there is an urgent need for novel treatment strategies. The MAPK and PI3K signaling pathways, key molecular drivers found to be hyper-activated in UM, converge on the MNK1/2-eIF4E and mTORC1/2-4EBP axes. Here, we demonstrate that the pharmacologic inhibition of MNK1/2 in combination with an mTOR inhibitor impairs clonogenic outgrowth and UM cell invasion. Using proteomic analyses, we reveal that combined MNK1/2 and mTOR inhibition disrupts ER-to-Golgi protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. We further uncover that the knockdown of RAB1A blocks liver metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. Finally, we show that RAB1A expression reshapes the surfaceome by increasing the abundance of plasma membrane proteins associated with poor overall survival in UM, highlighting its potential as a biomarker. This study identifies protein vesicle transport as an unrecognized vulnerability in UM and supports a mechanistic rationale for targeting MNK1/2 and mTOR in metastatic UM.